It has been more than 70 years since the U.S. Public Health Service began its study into the effects of syphilis on 399 human test subjects -- all of them black, all of them poor and most of them illiterate. When the infamous Tuskegee experiments finally came to light in 1972, the public at last learned the horrible truth.
The men in the Tuskegee study were never told they had syphilis, nor were they told the real purpose behind their participation in the experiment. Worse, they were systematically denied treatments that would have eased their suffering. In the annals of U.S. medical history, the Tuskegee experiments have become synonymous with ethical misconduct at its worst. The federal government assured the public that malpractice of this sort would never happen again. Sadly, however, it has.
Beginning in 1997, a team of researchers from The Johns Hopkins University, generously sponsored by the National Institutes of Health, conducted a clinical trial of the drug nevirapine in Uganda. Known as HIVNET 012, the researchers sought to prove that the anti-retroviral drug was safe and effective in preventing the transmission of the deadly AIDS virus from pregnant mothers to their newborn babies. According to the NIH, approximately 800,000 children worldwide became infected with the human immunodeficiency virus -- the organism that causes AIDS -- through mother-to-child transmission in 2002.
In 1999, the researchers published their findings: One dose of the drug nevirapine, given to a mother shortly before delivery, and once to her newborn, significantly reduced the incidence of HIV transmission to the child. The World Health Organization affirmed its support of this simple and inexpensive regimen. The medical community quickly adopted nevirapine as the drug of choice for pregnant HIV infected women in resource-poor countries.
Yet, as with the Tuskegee experiments, something went horribly wrong. In 2002, an audit of the HIVNET 012 trial raised questions about the validity of the study data. According to independent auditors, medical records of study participants could not support the published results, and numerous violations of the study protocol occurred without written explanation.
The Hopkins researchers admitted they lacked familiarity with the rudiments of Good Clinical Practice, the universally accepted standards for the conduct of medical experiments on human subjects. These standards protect trial participants from abuse and help to ensure study data are a truthful reflection of what was observed during the experiments.
The researchers have acknowledged that possibly thousands of adverse events went unrecorded due to poor or non-existent record keeping. An adverse event is defined in the Food and Drug Administration regulations as "any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product ..." The collection and analysis of such events form the very basis for assessing drug safety in humans.
Furthermore, HIVNET 012 auditors noted it was common practice for the researchers to assess adverse events based on second-hand or third-hand accounts observed by other, less-qualified staff, rather than seeing the study participants themselves. Even more alarming, the researchers expressed ignorance of the safety-reporting regulations, which had been incorporated into their own study protocol.
In short, the HIVNET 012 study violated some of the most elemental standards of clinical research, rendering the results -- especially those pertaining to drug safety -- invalid.
The abominable conduct of HIVNET 012 rendered the study useless for nevirapine's manufacturer, Boehringer Ingelheim, of Ingelheim, Germany. Upon learning of the results, the company withdrew its application to the FDA to market the drug for preventing the transmission of HIV. South Africa's regulatory authority, the Medicines Control Council, declared the HIVNET 012 study no longer a reliable basis on which to grant its provisional approval of nevirapine.
Nevertheless, the NIH hailed HIVNET 012 as a great success. Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, called the study "a very important public health breakthrough." Fauci aggressively promoted nevirapine to the White House, apparently never disclosing to officials the serious deficiencies of the study.
On June 19, 2002, in a White House ceremony attended by Senate Majority Leader Bill Frist, R-Tenn., Secretary of Health and Human Services Tommy Thompson and Secretary of State Colin Powell, President George W. Bush announced nevirapine therapy would become a pillar of his $500 million initiative to prevent maternal-to-child transmission of HIV.
A year later, during his State of the Union address, the president unveiled his $15 billion African AIDS program. Nevirapine figured prominently in this effort. Congress dutifully approved the president's plan without ever questioning the growing body of evidence that nevirapine can create drug-resistant mutations of the AIDS virus in as many as half of the people who take just one dose.
Fearing that the disclosure of the shoddy Uganda study could damage the reputations and credibility of some of the leading lights in AIDS research, the NIH embarked upon an elaborate effort to cover up the HIVNET 012 fiasco. The cover-up succeeded in fooling most of the AIDS scientific community, including the World Health Organization and many prominent AIDS-activist organizations. Under pressure from countries desperate for an AIDS victory, the WHO reaffirmed its support for the trial and its questionable findings.
The NIH has stubbornly defended the nevirapine trial, conceding only that "the conduct of the study lacked the necessary documentation to support a request to the FDA to consider this study as a stand alone pivotal trial." The cover-up of serious ethical and scientific misconduct in the HIVNET 012 study continues to this day.
So how is it that a clinical trial's conduct can be deemed too poor to support the use of a drug in a developed nation but still be considered suitable enough to support its use in resource-poor nations?
Like Tuskegee, HIVNET 012's investigators targeted a vulnerable population and conducted their research to lower standards than would be tolerated in a more affluent population.
Also like Tuskegee, the researchers ignored ethical norms, in this case the 1964 Declaration of Helsinki, and permitted the interests of science to take precedence over the well-being of their human subjects.
There is little question the NIH violated ethical principles by allowing unqualified researchers to conduct the HIVNET 012 trial. That has been borne out by the researchers' sheer ignorance of the most fundamental regulations and guidelines that govern human research. The resulting sloppiness in HIVNET 012's conduct, creating what most certainly should be considered invalid data, is a further violation of the tenet that human research must be performed properly in order to be considered ethical.
Is it no wonder the truth about HIVNET 012 has been buried?
After all, there is much at stake. There is the reputation of the investigators and their prominent institution, The Johns Hopkins University, which authored HIVNET 012's results and conclusions in a prominent medical journal.
Likewise, there is the reputation of the HIV Prevention Trials Network, which provided the operational support (or lack thereof) to the trial. There also is the reputation of the NIH leadership and its scientists, who should have monitored the study more closely. At the very least, they should not have awarded an international clinical research grant to physicians whose clinical research skills were unproven.
Most important, there is the reputation of the NIH itself. As the United States' leading medical research institution, the NIH is looked to by scientists and clinicians around the world as the pace-setter in scientific research. It is expected to exemplify the highest standards for scientific integrity and to produce results that are both credible and sustainable. Sadly, this all must now be called into question.
It was not long after Fauci successfully persuaded President Bush to invest his prestige and that of the U.S. government in nevirapine that the White House more than doubled the research budget of the National Institute of Allergy and Infectious Diseases. It soared from just over $2 billion annually in fiscal year 2001 to more than $4.3 billion in FY 2004. Having covered-up shoddy research, Fauci's NIAID then was awarded principal authority over the United States' civilian bio-defense effort by a grateful administration.
Only within the past year have whistleblowers within the NIH stepped forward with information suggesting a widespread cover-up of the HIVNET 012 clinical trial. Yet, instead of acknowledging their errors, the NIH bureaucracy has tried to silence its critics through intimidation, false accusations, character assassination and job termination.
Congress is reviewing hundreds of documents and the sworn testimony of a number of NIH officials that substantiate the allegations made by the whistleblowers. One senator has asked the Department of Justice to launch a criminal investigation into the HIVNET 012 debacle and the subsequent reprisals against NIH whistleblowers.
The NIH has commissioned The Institute of Medicine, a branch of the National Academy of Sciences, to investigate HIVNET 012. However, this review serves only to perpetuate the cover-up. Most of the IOM panel members have conflicts of interest that call into question their objectivity. By receiving research funding from the NIH, these individuals are unlikely to jeopardize their own standing with the institution.
Not surprising, few knowledgeable critics of the HIVNET 012 study have been asked to appear before the review panel. The terms of reference for the inquiry are so narrowly written, it will be impossible to draw any meaningful conclusions from the effort. Instead of addressing the failed NIH research process, reprisals against whistleblowers and the cover-up, the IOM team will address only the validity of the data from a scientific standpoint. This is not what the public interest requires.
The specter of Tuskegee has returned to government-sponsored clinical trials. Congress and the Bush administration need to launch a truly untainted investigation immediately into the pervasive scientific misconduct in the NIH's AIDS research program.
Going forward, Congress must exercise appropriate oversight over how taxpayer dollars are being used to subsidize substandard clinical trials -- actions that ultimately imperil the health and safety of Americans. There must be consequences for NIH researchers and managers who knowingly violate the rules, shave the truth and distort clinical data. Without true accountability, the scientific conclusions emanating from NIH research henceforth will be suspect.
Whistleblowers who expose failings in the federal research system must be protected. Their disclosures should be safeguarded and their careers insulated. The NIH must dramatically improve its monitoring of clinical trials and demand the highest level of good clinical practice.
Last, Africans must no longer be treated simply as test subjects bound to serve the ambitions of foreign researchers. They must be granted research protections equal to those afforded to Americans.
The controversy over nevirapine is but one example in a system that is sorely broken. Without a thorough overhaul of NIH-sponsored clinical trials, there are sure to be more Tuskegees in our future and with them a steady lowering in the standard of American medicine.
(Rand H. Fishbein, Ph.D. is executive director of HonestDoctor.org. He is a former professional staff member of the U.S. Senate Appropriations Committee and former special assistant for national security affairs to Sen. Daniel K. Inouye, D-Hawaii. The opinions expressed in this essay are based on documentation uncovered in connection with the case of Jonathan M. Fishbein, M.D. vs. the Department of Health and Human Services. Jonathan Fishbein is Rand Fishbein's brother. Rand Fishbein can be contacted through the Web site: HonestDoctor.org.)
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